Neuroblastoma, a tumor arising from embryonic neural crest, is the most common extra-cranial solid tumor of childhood, and less than 40% of children with high-risk features survive despite intensive treatment. Hypothesis: New tumor-targeted therapies that are non-cross resistant with standard chemotherapy and have been validated in pre-clinical studies will induce responses in patients with refractory tumors and improve outcome. Specific Aims: 1) To establish the tolerability and efficacy of [131]l-MIBG (targeting the norepinephrine transporter) with hematopoietic stem cell support when combined with chemotherapy, novel biologies, and/or radiosensitizers with combinatorial pre-clinical activity against resistant neuroblastoma; 2) Define rational combinations of agents that target key molecules relevant to tumor pathways and/or to tumor-microenvironment interactions that may be combined with standard cytotoxic agents to maximize efficacy against neuroblastoma, with pharmacokinetic and pharmacodynamic validation at the MTD; 3) Develop biomarker and semi-quantitative imaging technologies that provide additional neuroblastomaspecific endpoints to evaluate response to therapies. Methods and Interactions: We will focus on combination therapy that has specific rationale for neuroblastoma, utilizing Phase I data for single agents tested against a broader spectrum of solid tumors in combination with laboratory data from Projects 1-3 and Pre-Clinical Testing Core D. Examples of agents to be tested include MlBG with radiosensitizers and chemotherapy, anti-IL6 with metronomic cyclophosphamide and zometa (Project 1), immunotherapy (Project 2), PIS kinase inhibitors (Project 3). NANT (New Approaches to Neuroblastoma Therapy), is our consortium of 15 institutions that will conduct the clinical trials with the support of the cores for administrative research support, histopathology, pre-clinical testing, biostatistics, as well as the NANT Operations Center. The NANT works in very close cooperation with the Children's Oncology Group (COG), CTEP and the FDA, and industry sponsors with the goal of bringing the most promising agents from our Phase I trials forward into Phase II and then national Phase III trials.